Strategies to reduce the risk of fetal infection are of critical importance during pregnancy, where maternal to fetal transmission of microbes can have devastating consequences to the developing embryo, ranging from fetal infection, induced preterm delivery, structural or functional congenital anomalies, miscarriages and stillbirths (Ornoy and Tenenbaum, Reprod Toxicol 21, 446-457, 2006; Silingardi et al., Am J Forensic Med Pathol 30, 394-397, 2009; Euscher et al., Obstet Gynecol 98, 1019-1026, 2001). Additionally, pathogenic infections can compromise maternal health and jeopardize the pregnancy even in the absence of fetal transmission. The physical barrier interfacing the maternal and fetal blood systems within human hemochorial placenta villi include the trophoblast bilayer, basement membrane, stromal cells and fetal capillary endothelial cells. The multinucleated, terminally differentiated villous syncytiotrophoblasts are bathed directly in the maternal blood, and mediate the crucial exchange of gases, nutrients, and waste products between the mother and fetus, produce crucial hormones, and immunologically guard the developing fetus. These cells, along with the less differentiated cytotrophoblasts, constitute the first line of feto-placental defense against invading microbes.
Intrauterine transmission of viruses is likely to occur by at least four potential routes: (a) transmission across the placental villous trophoblasts by hematogenous spread or ascending infection, (b) placental transfer of infected macrophages from the maternal blood, (c) transfer of viruses via paracellular routes and/or (d) transmission of viruses from the infected maternal endothelial microvasculature to endovascular extravillous cytotrophoblasts. In general, little is known regarding the defense mechanisms employed by placental trophoblasts to defend against viral infections. Additionally, as antiviral therapeutics are generally ineffective in preventing intrauterine viral infections, elucidating the nature of these mechanism(s), as well as the underpinnings of viral counter-measures, is critical for designing therapeutic strategies aimed at preventing fetal and maternal viral disease.
Mammalian cells utilize diverse defense mechanisms to combat microbial pathogens. One crucial mechanism is the induction of autophagy, an evolutionarily conserved lysosomal degradation pathway that has been associated with an array of cellular functions, including cell death (Beaulation and Lockshin, J Morphol 154:39-57, 1977; Liang et al., Nature 402:672-676, 1999), tumorigenesis (Qu et al., J Clin Invest 112:1809-1820, 2003), and neurodegeneration (Hara et al., Nature 441:885-889, 2006; Komatsu et al., Nature 441:880-884, 2006). Autophagy also degrades intracellular foreign microbial invaders (a process sometimes referred to as xenophagy or virophagy). The cascade of events that culminate in autophagy begin with the formation of a double membrane organelle, the autophagosome, and ends in the degradation of engulfed material via the fusion of autophagosomes with late endosomes and/or lysosomes. The degradation of microbes via the fusion of autophagosomes with lysosomes is a key component in the antimicrobial effects of autophagy, yet the sequestration of viruses into autophagosomes can also direct MHC class II presentation (English et al., Nat Immunol 10:480-487, 2009), the production of antiviral type I interferons downstream of toll-like receptor 7 engagement (Lee et al., Science 315:1398-1401, 2007), and even altered T-cell signaling (Nedjic et al., Nature 455:396-400, 2008). It is becoming clear that autophagy functions at the crossroads of many aspects of cell survival, and is likely a fundamental component of antiviral signaling.